REVIEW

CURRENT
OPINION Albumin in critically ill patients: the ideal colloid?
Pietro Caironi a,b, Thomas Langer b, and Luciano Gattinoni a,b

Purpose of review
The use of albumin-containing solutions in critically ill patients has been recently revisited, following
evidence on harmful effects of synthetic colloids, and novel randomized controlled trials (RCTs) in sepsis.
Here, we review the most recent findings on albumin administration in acutely ill and septic patients.
Recent findings
The revision of Starling’s theory on microvascular fluid dynamics has highlighted the role of albumin in
preserving intravascular compartment volume. In cirrhosis, albumin may be important in maintaining
immune system reactivity and cardiac contractility. Preliminary analyses indicate albumin as beneficial in
patients with burn, while being associated with increased risk of acute kidney injury after cardiac surgery.
The first RCT (ALBIOS trial) testing the efficacy of albumin replacement in severe sepsis did not show a
survival benefit associated with albumin, although observing at post-hoc analysis a benefit in septic shock.
All the eight meta-analyses performed on albumin in sepsis reveal an absence of harm, and likely a benefit
lower than expected, whereas suggesting an advantage, to be verified, in septic shock.
Summary
Further studies are needed to clarify physiology and clinical impact of albumin in critically ill patients,
considering specific phenotypes and secondary outcomes other than survival, yet clinically relevant.
Keywords
albumin, critically ill, fluids, sepsis

INTRODUCTION randomized controlled trials (RCTs) on the use of

&&

In humans, albumin is the colloid molecule most
representative in the extracellular space, being cru-
cial in regulating the physiology of microvascular
fluid dynamics [1]. Moreover, albumin, being one of
the molecules synthesized by the liver with the
highest energy requirement, acts as an important
player of several secondary functions, including
transportation of endogenous and exogenous mol-
ecules, antioxidant and anti-inflammatory proper-
ties [2,3]. This is why its use as intravenous solution
has been widely applied to critically ill patients,
until the publication of a highly ranking meta-
analysis in 1998 has warned against its use [4]. As
the history of medicine goes on, and more solid
evidence becomes available, the publication of the
SAFE trial has finally clarified its potential disadvan-
tages [5] and advantages [6] in specific categories of
critically ill patients, while assuring its safety in the
heterogeneous population [7]. Recently, an increas-
ing attention to the use of albumin-containing
solutions in patients admitted to intensive care
units (ICUs) has resumed, mainly for two reasons:
first, the evidences that most of the available syn-
thetic colloids may be harmful in critically ill
patients [8–10]; second, the conclusions of large
albumin in severe sepsis [11,12 ]. In the current
manuscript, we would like to review the recent
findings related to the physiological rationale of
using albumin in critically ill patients, and the last
evidence available on its clinical impact.
ALBUMIN AND VASCULAR COLLOID AND
OSMOTIC PRESSURE
Oncotic properties characterizing the intravascular
space depend on the concentration of albumin in the
capillaries, in which the membrane separating intra-
vascular and extravascular spaces is impermeable to
a
Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Fon-
dazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Università
degli Studi di Milano and bDipartimento di Anestesia, Rianimazione ed
Emergenza Urgenza, Fondazione IRCCS Ca’ Granda – Ospedale
Maggiore Policlinico, Milan, Italy
Correspondence to Pietro Caironi, MD, Dipartimento di Fisiopatologia
Medico-Chirurgica e dei Trapianti, Fondazione IRCCS Ca’ Granda –
Ospedale Maggiore Policlinico, Università degli Studi di Milano, Via F.
Sforza 35, 20122 Milano, Italy. Tel: +(02) 5503-3232/3231; fax: +(02)
55033230; e-mail: pietro.caironi@unimi.it
Curr Opin Crit Care 2015, 21:302–308
DOI:10.1097/MCC.0000000000000223

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August 2015

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 Albumin in critically ill patients: the ideal colloid? Caironi et al.
KEY POINTS

Albumin is one of the main determinants of the integrity
of the endothelial glycocalyx, thus cooperating in the
maintenance of the intravascular compartment volume.

In decompensated cirrhosis, albumin may reverse
immune-paralysis associated with prostaglandin E2
release, and preserve myocardial contractility by
blocking inducible nitric oxide synthase.

Although its administration in critically ill patients may
have heterogeneous effects, human albumin
administration may be advantageous in burn patients,
whereas it may increase the risk of acute kidney injury
in patients after cardiac surgery.

In severe sepsis, the ALBIOS trial did not show any
survival benefit associated with albumin administration,
while reporting a reduction in 90-day mortality in the
subgroup of patients with septic shock, at post-hoc and
not predefined analysis.

All the eight meta-analyses performed on the use of
albumin in sepsis have shown no improvement in
survival as associated with its administration in patients
with sepsis or severe sepsis, while suggesting a
beneficial effect in patients with shock, yet to
be confirmed.
solutes (mainly albumin) and permeable to the sol-
vent (water) [13]. Normal concentration of albumin,
in humans, equals 35–55 g/l [3], corresponding to
about 0.54–0.85 mmol/l. The osmotic pressure
because of a solute equals the pressure that the solute
would exert if present in gas-phase with the same
number of particles occupying the same volume the
solution occupies. Therefore, 0.54 mmol of albumin
would exert a pressure of 9.2 mmHg. In fact, as
1 mmol occupies about 22.4 ml at 760 mmHg,
0.54 mmol will occupy 12.1 ml. Since according to
the Boyle’s law, if the temperature is constant, the
‘pressure-time-volume’ product for a constant
amount of gas is constant [14], 12.1 ml of albumin
in ‘gas-phase’ will exert a pressure equal to
12.1 ml  760 mmHg ¼ 9196 ml  mmHg, which, in
1–l solution will equal 9.2 mmHg. Indeed, if the
oncotic pressure of a 0.538 mmol/l albumin solution
would be measured by employing an oncometer, a
value of 9.2 mmHg would be actually measured. In
plasma, however, the oncotic pressure is lower than
that measured or theoretically computed, simply
because, even in healthy subjects, the permeability
of the endothelial barrier to albumin widely varies,
depending on different organ systems (Table 1)
[15,16]. In diseased states, the altered capillary per-
meability nullifies the oncotic properties of albumin
at different extent. Therefore, as suggested originally
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Table 1. Data represent values of reflection coefficient for
albumin in different organs, in healthy humans
Organ Reflection coefficient
Skeletal muscle 0.9–0.95
Lung 0.50–0.65
Intestine 0.80
Subcutaneous space 0.80
Liver 0.0–0.05
Spleen 0
Brain 1.0
Modified from [16].
by Starling [17], there are two forces within the
capillary microcirculation acting in an opposite man-
ner: the hydrostatic pressure, tending to push the
‘solvent’ out of the capillaries, and the oncotic pres-
sure, tending to re-absorb the ‘solvent’ from the
interstitial space into the capillaries. When the two
pressures are equal, no water transfer occurs, whereas
it may be positive (leading to interstitial fluid
accumulation) in case of hydrostatic pressure greater
than oncotic pressure, and vice versa. The classical
Starling’s view has been revised in the last 10 years,
after the identification of the glycocalyx as a crucial
structure regulating transvascular fluid exchange
[18]. According to this paradigm, the impermeability
to albumin occurs at the endothelial glycocalyx layer.
Nonetheless, in our opinion, it does not modify
essentially the Starling’s concept, at least at the ven-
ular side. This is quite evident in full-blown sepsis,
wherein the capillary permeability is altered at such
extent that the amount of fluid given to achieve a
predefined hemodynamic target is similar, whether
including crystalloids, with or without albumin, or
synthetic colloids [19 ].
&
SECONDARY FUNCTIONS OF HUMAN
ALBUMIN
Albumin has well-known physiological secondary
properties [2]. Within its molecular structure, the
thiol residues provide antioxidant properties, buf-
fering the harmful actions of nitric oxide and free
oxygen radicals [20,21], whereas the carboxyl ter-
minals of histidine make albumin the most efficient
buffering molecule of the extracellular acid-base
equilibrium [22]. These functions are operative as
long as the thiol and histidine groups are function-
ally active [23]. Otherwise, despite ‘normal’ plasma
albumin concentration, these properties may be
functionally inactive [24 ].
&
Two novel secondary functions have been
recently investigated. O’Brien et al. [25 ], in an
&
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Intravenous fluids
extensive translational study, investigated the role
of the cyclooxygenase-derived eicosanoid prosta-
glandin E2 (PGE2) as a mediator of the immunosup-
pressive state characterizing advanced cirrhosis. In
their study, the authors observed that plasma of
patients with acute decompensated liver cirrhosis
had elevated circulating levels of PGE2, which are
able to suppress the pro-inflammatory and the
bacteria-killing capacity of macrophages. Albumin
administration, by reducing circulating PGE2 levels,
significantly improved the plasma-induced impair-
ment of macrophage pro-inflammatory actions,
indicating that albumin-containing solutions may
attenuate the PGE2-mediated immunosuppression
and the associated risk of secondary infections. In
another study, Bortoluzzi et al. [26] elucidated the
effects of albumin on cardiac contractility in an
experimental model of decompensated cirrhosis.
The investigators observed that after the develop-
ment of cirrhosis, cardiac contractility was impaired
in association with an increased inducible nitric-
oxide synthase (iNOS) and TNF alpha protein
expression. After administration of albumin, but
not of synthetic colloids, these cellular alterations,
in parallel with cardiac functionality, returned to
normal levels, suggesting a potential for albumin
acting as a positive inotropic agent by contrasting
the effects of iNOS and TNF alpha-pathways.
Although these findings relate to cirrhotic patients,
their transferability to acutely critically ill patients
may open possible novel therapeutic options of
great potential.
ALBUMIN-CONTAINING SOLUTIONS AND
EFFECTS ON ACID-BASE EQUILIBRIUM
According to Stewart’s approach to acid-base equi-
librium, pH is regulated by the strong ion difference
(SID), defined as the difference between strong
cations and anions, the partial pressure of carbon
dioxide and the concentration of nonvolatile weak
acids (mainly albumin and phosphates) [27]. Infu-
sion of crystalloid solutions affects plasma pH
according to the difference between plasma
bicarbonate concentration (HCO3) and the SID
of the infused crystalloid (SIDINF) [28,29]. If SIDINF
is greater than baseline HCO3 concentration, pH
will increase (generating alkalosis). If SIDINF is lower
than baseline HCO3 concentration, pH will
decrease (generating acidosis). If SIDINF approxi-
mates the baseline concentration of HCO3, pH will
eventually remain constant, regardless of the
amount of the infusion, and the degree of dilution
&&
[30 ].
Colloid solutions are, de facto, crystalloid
solutions containing oncotic macromolecules.
304 www.co-criticalcare.com
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Schematically, based upon their electrical character-
istics, colloid molecules may be either characterized
by a neutral activity, such as starches and dextrans,
or by surface negative charges, such as gelatin
&&
and albumin [30 ]. Consequently, starches and
dextrans do not interfere with the electrochemical
balance, and solutions containing starches and dex-
trans follow simple rules described for crystalloid
solutions. On the contrary, gelatins and albumin
have surface negative charges. Within the frame-
work of Stewart’s approach, these molecules belong
to the category of weak acids, and therefore have per
&&
se an acidifying effect [30 ]. Commercially available
albumin solutions differ in electrolyte composition,
mainly due to the specific purification process
applied for human plasma and the preparation of
solutions with different albumin concentration
(mainly 4%, 5% and 20%), and, consequently, differ
from endogenous albumin, in terms of half-life and
antioxidant properties [31]. Most of studies per-
formed describe, in fact, the development of mild
metabolic acidosis after the infusion of albumin
&
preparations [32,33 ], although this effect is prim-
arily because of the specific electrolytic composition
(i.e. the SID of the solvent), rather than the effect of
the albumin molecule [34].
ALBUMIN IN CRITICALLY ILL PATIENTS
Since the late 1940s [35], intravenous solutions
containing albumin have been extensively admin-
istered to critically ill patients, despite conflicting
&&
results on its effect on survival [36 ].
&
Navickis et al. [37 ] performed a meta-analysis
on four randomized and four nonrandomized stud-
ies on burn shock resuscitation with albumin
solutions. After the exclusion of two studies at high
risk of bias, the authors observed a significant
reduction in mortality and in incidence of abdomi-
nal compartment syndrome in patients receiving
albumin. Despite such promising findings, the pauc-
ity of available data and the poor quality of RCTs
warrant confirmatory studies. Similarly, in another
&
meta-analysis, Kitsios et al. [38 ] investigated the
effect of the combined administration of albumin
and furosemide to overcome diuretic resistance in
patients characterized by hypoalbuminemia. The
authors observed only a minor and transient
increase in urinary output and sodium excretion
rate in patients receiving the co-administration of
albumin and furosemide, as compared with those
receiving only loop-diuretics, whereas intermediate
outcomes did not differ between the two strategies.
&
Uhlig et al. [39 ] performed a meta-analysis to
evaluate the impact on mortality and lung function
of the use of either crystalloid or albumin-
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 Albumin in critically ill patients: the ideal colloid? Caironi et al.
containing solutions in adult acute respiratory dis-
tress syndrome (ARDS). According to their analysis,
pooled risk of death was equal between the two
groups, whereas oxygenation appeared to be
superior in patients receiving albumin. The authors
interpret this finding as the result of a reduced
alveolar-capillary leakage, although this effect did
not translate in an improvement of survival. Lastly,
&&
Frenette et al. [40 ] performed a retrospective
cohort study including patients undergoing on-
pump cardiac surgery to assess the risk of acute
kidney injury (AKI) associated with either albumin
or starches administration. The authors found albu-
min-containing solutions to be associated with a
dose-dependent risk of AKI development. In the
context of previous observational [41,42] and recent
&&
findings observed in the ALBIOS trial [12 ], with no
evidence of an increased risk of AKI even with the
use of hyperoncotic albumin solutions, this issue
merits further investigations.
ALBUMIN ADMINISTRATION IN SEPSIS:
THE LARGE RANDOMIZED CONTROLLED
TRIALS
Two large RCTs have investigated so far the efficacy
of albumin administration in patients with severe
sepsis or septic shock: the EARSS study (Early Albu-
min Resuscitation during Septic Shock), published
only in form of an abstract [11], and the ALBIOS trial
(Albumin Italian Outcome Sepsis), published the
&&
last year [12 ]. The EARSS trial (NCT00327704), a
French multicenter, open-label RCT, enrolled 794
patients with early septic shock, randomized to
receive either 20% albumin or isotonic saline for
the first 3 days of fluid resuscitation. The authors
reported no significant difference in mortality rates
between the two groups (24.1% vs. 26.3%).
In the ALBIOS trial, we investigated the efficacy
of albumin replacement, aimed at maintaining a
targeted serum albumin level equal to or greater
than 30 g/l, in addition to crystalloids during the
first 28 days after randomization in patients with
severe sepsis or septic shock, as compared with
&&
crystalloids alone [12 ]. The study enrolled, from
100 Italian ICUs, 1818 patients within 24 h from the
development of severe sepsis. Albumin adminis-
tration in addition to crystalloids was associated
with a higher mean arterial pressure and a lower
net positive fluid balance over the first 7 days, as
compared with the administration of crystalloids
alone, despite a similar daily amount of total admin-
istered fluids. Nonetheless, at 90 days, mortality
rates appeared similar between the two groups
(41.1 vs. 43.6%, P ¼ 0.29, respectively), as were all
the secondary outcomes assessed, with the
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exception of the time to suspension of vasoactive
agents, being shorter in the albumin as compared
with the crystalloid group. In contrast, in a post-hoc
subgroup analysis on patients with shock at the time
of enrolment, we observed a significant reduction in
90-day mortality rate in the albumin group as com-
pared with the crystalloid group (N ¼ 1121, 43.6 vs.
49.9%, P ¼ 0.03). Taken together, these findings
showed that albumin supplementation in addition
to crystalloids to correct hypoalbuminemia does not
improve 90-day survival in patients with severe sep-
sis, as compared with the use of crystalloids alone. In
contrast, they suggest a possible benefit in the sub-
group of patients with septic shock. As noted by
&
Flannery et al. [43 ], the trial presented certain limita-
tions, mainly relying on the un-predefined nature of
the post-hoc analysis performed, and the open-label
design. Nonetheless, it is worth mentioning that the
significant reduction of 90-day mortality in patients
with shock was still confirmed even after adjustments
&
for clinically relevant variables [44 ].
ALBUMIN ADMINISTRATION IN SEPSIS:
THE META-ANALYSES
Since the first meta-analysis on the use of albumin in
patients with sepsis [45], several meta-analyses have
been added to this theme, especially after the con-
clusion of the ALBIOS trial (Table 2) [45–
& && && & &
47,48 ,49 ,50 ,51 ,52 ]. Of note, based upon data
from essentially only two large-scale RCTs evaluat-
ing the efficacy of albumin administration in
&
patients with sepsis [11,44 ], already eight different
meta-analyses have been published, of which five in
the last year.
As a potential limitation of the meta-analytic
methodology, the analyses performed differ in
many aspects, most of them affecting study
inclusion, and leading to the analysis of hetero-
geneous populations. First, the targeted population
varies from patients with severe sepsis or septic
& && &
shock [47,48 ,49 ,52 ], to those with sepsis of any
severity, without predefined subgroup analysis
[45,46]. Moreover, some studies included both adult
&
and pediatric patients [45,51 ]. Second, the outcome
measurements, and the time of its assessment, are
variable between studies. Third, the treatment
chosen for the comparison was often not homo-
geneous, including either the use of crystalloids
& &
[48 ,52 ], or the use of any fluid different from
albumin (i.e. both crystalloids and synthetic
&& && &
colloids) [45–47,49 ,50 ,51 ]. Finally, many stud-
ies differ in the study design, doses of albumin
administered, time of fluid intervention, and albu-
min manufacturers. At the same time, even the
methodology applied and the quality assessment
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 306
Table 2. Summary of the meta-analyses available until the preparation of the present review, testing the efficacy of albumin administration in patients with sepsis

Number of Types of
Year of studies included studies
Authors publication Inclusion criteria (sample size) Comparison included Primary outcomes Results; OR or RR (95% CI)

Delenay et al. 2011 [45] Sepsis of any severity 17 (N ¼ 1977) Albumin vs. RCTs All-cause mortality at the Sepsis: OR 0.82 (0.67–1.00),
Intravenous fluids

(adults and pediatrics). crystalloid longest follow-up P ¼ 0.047

Predefined subgroups or colloid available
Cui et al. 2012 [46] Sepsis of any severity 14 (N ¼ 1729) Albumin vs. RCTs All-cause mortality Sepsis: OR 0.87 (0.71–1.07),
(adults) crystalloid P ¼ 0.18
or colloid
Leitch et al. 2013 [47] Severe sepsis 9 (N ¼ 1435) Albumin vs. RCTs All-cause mortality at the Severe sepsis: RR 0.90

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crystalloid longest follow-up (0.79–1.02), P ¼ 0.11
or colloid available
&
Wiedermann et al. 2014 [48 ] Severe sepsis (adults) 3 (N ¼ 3791) Albumin vs. Large-scale All-cause mortality at the Severe sepsis: RR 0.92
crystalloid RCTs longest follow-up (0.84–1.00), P ¼ 0.046
available
&&
Rochwerg et al. 2014 [49 ] Severe sepsis (adults). 14 (N ¼ 18916) Any fluid RCTs All-cause mortality at the Severe sepsis: albumin vs.
Predefined subgroup strategy longest follow-up crystalloids, OR 0.83
and network meta-analysis compared available (0.65–1.04)
to a different
fluid strategy
&&
Patel et al. 2014 [50 ] Sepsis of any severity 16 (N ¼ 4190) Albumin vs. RCTs All-cause mortality at the Sepsis: RR 0.94 (0.87–1.01),
(adults). Predefined crystalloid longest follow-up P ¼ 0.11; severe sepsis
subgroups or colloid available without shock: RR 0.95
(0.85–1.06), P ¼ 0.35
(N ¼ 2070); septic shock:
RR 0.92 (0.83–1.02),
P ¼ 0.10 (N ¼ 1962)
&
Jiang et al. 2014 [51 ] Sepsis of any severity 15 (N ¼ 6998) Albumin vs. RCTs All-cause mortality at the Sepsis: RR 0.94 (0.87–1.02),
(adults and pediatrics). crystalloid longest follow-up P ¼ 0.15; severe sepsis without
Predefined subgroups or colloid available shock: RR 0.95 (0.85–1.07),
P ¼ n.s; septic shock: RR 0.89
(0.80–0.99), P ¼ 0.04
&
Xu et al. 2014 [52 ] Severe sepsis (adults). 6 (N ¼ 3658) Albumin vs. RCTs and All-cause mortality Severe sepsis: OR 0.88
Predefined subgroup crystalloid parallel trials (including 28-, 90-day (0.76–1.01), P ¼ 0.08; shock:
mortality, or at other OR 0.81 (0.67–0.97), P ¼ 0.03
time points)

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CI, confidence interval; OR, odds ratio; RCT, randomized controlled trial; RR, relative risk.

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August 2015

 Albumin in critically ill patients: the ideal colloid? Caironi et al.
of studies included vary between meta-analyses
&& &
[50 ,52 ].
What can we derive from these data? Evidence
gathered so far indicates that in a general population
of patients with severe sepsis, the administration of
albumin-containing solutions is not associated
with a significant reduction in mortality rate
(at least until the generally accepted follow-up time
of 90 days), as suggested by the two large concluded
&&
RCTs [11,12 ]. Of note, the analyses performed
have always observed a relative risk variation in
favor of the treatment with albumin, although
not achieving (but being close to) a statistical sig-
nificance. Such consistency of findings suggests,
with a relatively high degree of certainty, that albu-
min administration to these patients does not cause
harm, and that the beneficial effects related to it, if
any, may be quantitatively smaller than expected.
At the same time, the same evidence indicate that
there might be a beneficial effect related to albumin
in the subgroup of patients with septic shock, as
observed also in the post-hoc analysis from the
&& &
ALBIOS trial [12 ,44 ], and that this hypothesis
merits further confirmations. Such considerations
gain even more importance when evaluating the
potential cost-effectiveness of employing albumin-
containing solutions in critically ill patients, and
patients with severe sepsis or septic shock, because
of their relative high cost. In fact, although as esti-
mate, recent cost-effectiveness analyses have
suggested that albumin administration may be the
most cost-effective treatment, as compared with
other colloids or crystalloids, in septic patients,
when considering all the medical costs implied in
patient clinical treatment [53].
CONCLUSION
It is crucial to consider three further aspects, which
raise still unanswered questions. First, as most of the
evidence achieved so far has been focused on
mortality as primary outcome, it is conceivable that
secondary, and more physiological outcomes (such
as organ functions) will unveil different effects, still
clinically relevant, related to the use of albumin,
albumin being one of the most important physio-
logical extracellular proteins. Second, we still need
ad-hoc clinical studies testing aspects so far still not
investigated, such as the effects of different timing,
doses and rationales for albumin administration
&&
[36 ]. Third, based upon the wide variability of
phenotypes originating by the syndrome ‘sepsis,’
it is possible that specific categories of patients will
show a variability of effects related to albumin
administration, and possibly at follow-up time lon-
ger than those assessed.
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Is therefore albumin the ideal colloid for crit-
ically ill patients? With the exception of patients
with traumatic brain injury [5], ideally, the answer
may be ‘yes,’ but, in practice, we have no solid
clinical evidence for its cost-effective benefit, and,
more importantly, many questions to be answered.
Without being religiously believers of the benefit of
albumin administration in acutely ill patients, or
those with severe sepsis, we need to keep on study-
ing its physiological mechanisms of action, in the
attempt to individuate subgroups of patients, which
may benefit, or may even receive harm, from this
treatment. Based upon simple notions of physiology
and the clinical evidence available, the premises are
still promising.
Acknowledgements
We would like to thank Eleonora Carlesso, MSc, for her
assistance in the preparation of the present manuscript.
Financial support and sponsorship
This work was partially supported by funding from the
Italian Medicines Agency (AIFA, grant FARM6JS3R5,
2006) and from the Italian Ministry of Health (Ricerca
Finalizzata, grant RF-2011–02348358).
Conflicts of interest
P.C. has received honoraria for lectures from Grifols, CLS
Behring, B. Braun and Baxter. T.L. reported no conflicts
of interest. L.G. is on the Advisory Board of Grifols and
has received speaker’s honoraria from KCI, B. Braun,
Baxter, Grifols, and Kedrion.
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Recent Clin Trials 2014; 9:21–30.
Volume 21
Number 4
August 2015